The Children's Liver Disease Research and Education Network (ChiLDREN) provides unprecedented opportunities to improve outcomes of pediatric liver diseases worldwide. This proposed Clinical Center submission builds on a strong institutional record in patient enrollment, clinical and bench research, and diagnostic technology at the St. Louis Children's Hospital/Washington University School of Medicine (SLCH/WUSTL) by expanding enrollments to Arkansas Children's Hospital/University of Arkansas for Medical Sciences (ACH/UAMS), interacting with the resources of the Washington University Clinical and Translational Science Award and Queensland Institute for Medical Research, and collaborating with a pediatric primary care network (WU Pediatric/Adolescent Ambulatory Research Consortium). We will apply advanced imaging, pathology, and population analyses to the sophisticated multidisciplinary project required to tackle pediatric liver diseases. Our goals are embodied in the following Specific Aims: Aim I (Clinical Enrollment, Data Accrual, and Specimen (Collection) extends the highly effective SLCH/WUSTL enrollment effort to the active program at ACH/UAMS, generating a large referral base across the central US, that will collect data, sera, pathology samples and sophisticated images from >70 patients annually. We anticipate enhanced contribution to all protocols. Aim 2 (Develop Novel Diagnostic and Prognostic Strategies for ChiLDREN Diseases) tests the hypotheses that identifiable, possibly modifiable mechanisms leading to hepatic fibrosis, and that systematic and rigorous biomarker discovery studies will elucidate these processes, and that competing outcomes and neural network analyses will further define disease course. Aim 3 (Enhance practice quality, and Education) scrutinizes primary care practices and laboratory utilization in an attempt to accelerate identification and referral of infants with cholestasis, focussing on the critical events surrounding presentation, with the goal of defining, then reducing, the factors that hinder timely referral for biliary atresia. Aim 4 (Apply imaging methodologies to ChiLDREN diseases) amalgamates SLCH/WUSTL's advanced liver imaging capabilities to the study of childhood liver diseases, offering these to the Network. These highly matrixed Aims will be built on our enrollment strategies funded by this grant, augmented by existing and anticipated competitive funding, and dedicated WUSTL institutional support. By study conclusion, we intend to generate knowledge that will improve diagnosis, predict outcomes, guide intervention and improve provider practices in ChiLDREN diseases. Relevance: Children with liver disease present major challenges. These diseases are collectively important because of high morbidity, mortality, and public health impact. Management is often ineffective, with cirrhosis, liver failure and liver transplantation as common end-points. Advances in ability to diagnose, and discover causes and determinants of cirrhosis offer hope and potential to impact these outcomes. To achieve this, integration of research and clinical care via a collaborative research consortium is essential.